Thiepin derivatives

ABSTRACT

COMPOUNDS OF THE CLASS OF 2,3-DIHYDRO-1H-THIENO(2&#39;&#39;,3&#39;&#39;:2,3)(1) BENZOTHIEPINO (4,5-C)PYRROLE, 2,3-DIHYDRO1H-THIENO(3&#39;&#39;,2&#39;&#39;:2,3)(1)BENZOTHIEPINO(4,5-C)PYRROLE, AND THE N-ALLYL AND N-ALKYL DERIVATIVES THEREOF ARE PREPARED FROM 4,5-DISBROMOMETHYLTHIENO (3,2-B)(1) BENZOTHIEPIN OR 4,5-BISBROMOMETHYLTHIENO(2,3-B)(1)BENZOTHIEPIN AND AMINES, THESE COMPOUNDS AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE A DEPRESSANT EFFECT UPON THE CENTRAL NERVOUS SYSTEM AND ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPSITIONS.

United States Patent @flice 3,798,237 Patented Mar. 19, 1974 3,798,237 THIEPIN DERIVATIVES Hans Blatmer and Walter Schindler, Riehen, Basel-Land, Switzerland, assignors to Ciba-Geigy Corporation, Ardsley, N.Y.

No Drawing. Original application Dec. 16, 1970, Ser. No. 98,927, now Patent No. 3,682,959. Divided and this application June 15, 1972, Ser. No. 263,045

Int. Cl. A61k 27/00 US. Cl. 260-3325 3 Claims ABSTRACT OF THE DISCLOSURE Compounds of the class of 2,3-dihydro-1H-thieno- [2',3:2,3][l]benzothiepino[4,5 c]pyrrole, 2,3-dihydro- 1Hthieno [3,2' 2, 3] 1 benzothiepino [4,5 -c] pyrrole, and the N-allyl and N-alkyl derivatives thereof are prepared from 4,5-disbromomethylthieno[3,2-b] [1]benzothiepin or 4,5 bisbromomethylthieno[2,3 b][l]benzothiepin and amines, these compounds and the pharmaceutically acceptable acid addition salts thereof have a depressant effect upon the central nervous system and are active ingredients of pharmaceutical compositions.

This is a division of application Ser. No. 98,927, filed Dec. 16, 1970, now US. Pat. No. 3,682,959, issued Aug. 8, 1972.

The present invention relates to thiepin derivatives, to processes for their production, to pharmaceutical compositions comprising the compounds and to the use thereof.

More particularly, the present invention relates to compounds of the formula (i=3; XW Ll wherein one of the symbols x and y is a sulfur atom and the other a direct bond between the two adjacent carbon atoms, and

R is hydrogen, allyl or alkyl having at most four carbon atoms;

and the pharmaceutically acceptable acid addition salts thereof.

In the compounds of Formula I, R as alkyl group having at most four carbon atoms is, e.g., the methyl, ethyl, propyl, isopropyl, butyl, sec.butyl or isobutyl group.

Compounds of the Formula I and the pharmaceutically acceptable acid addition salts thereof have valuable pharmacological properties. They exert, in particular, on oral, rectal, or parenteral administration a depressant efiect upon the central nervous system. For example they reduce motility, inhibit conditioned reflexes, potentiate the effect of anaesthetics, lower the body temperature, exert an inhibiting action in the test de la traction and on the fighting mouse. They furthermore have in particular a muscle relaxing effect. Also antiemetic, adrenolytic and histamine-antagonistic actions can be shown. These properties of the compounds of Formula I are determined by selected standard tests in experimental animals [cp. R.

Domenjoz and W. Theobald, Arch. Int. Pharmacodyn. 120, 450 (1959), and W. Theobald et al., Arzenimittelforschung 17, 561 (1967)].

Thus, merely by illustration, it is demonstrated that 2-ethyl-2,3-dihydro 1H thieno[2,3':2,3]benzothiepino- [4,5-c]pyrrole, in form of the methane-sulfonate addition salt, reduces orientation motility of mice upon intraperitoneal administration in amounts of about 0.012 mg./kg.

The same compound, subcutaneously administered in amounts of about 0.5 mg./ kg. to mice, anaesthetized intraperitoneally with 40 mg./kg. of the short-acting anaesthetic N,N-diethyl-2-methoxy 4 allyl-phenoxyacetic acid amide, potentiates, i.e. prolongs the effect of the anaesthetic to a very significant extent.

The same compound, subcutaneously administered in amounts of about 0.26 mg./kg. to mice prevents about 50% of the animals hanging on to a wire with their front paws, from pulling up and gripping the wire with their hind paws (test de la traction).

Similar results are found with 2,3-dihydro-lH-thieno- [2,3':2,3][l]benzothiepino[4,5-c1pyrrole, the 2-methylsubstituted derivative thereof and the 2-methyl-,2-ethyland 2-butyl-substituted 2,3-dihydro-lH-thieno[3,2':2,3] l ]benzothiepino [3 ,4-c] pyrrole.

Although the methane sulfonate addition salts are preferred also other pharmaceutically acceptable acid addition salts can be used.

The pharmacological properties of the compounds of the invention in combination with a favorable low order of toxicity render them suitable for the treatment of states of tension and agitation of psychic and muscular genesis.

The compounds of the Formula I are produced according to the invention by reacting compound of Formula H.

H Br Br wherein X and Y have the meaning given in Formula I, with an amine of the Formula III,

R! N H H (In) wherein R has the meaning given under Formula I, and, optionally, converting the obtained reaction product with an inorganic or organic acid into an addition salt.

The bis-bromomethyl compound of Formula II is reacted with the free bases of the Formula 111 in the pres ence of a solvent. Suitable solvents are such which are inert under the reaction conditions, e.g. hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as chloroform, lower alkanols such as methanol or ethanol, ethereal liquids such as ether or dioxane, lower alkanones such as acetone, methyl ethyl ketone or diethyl ketone, as well as mixtures of such solvents.

In the reaction according to the invention of one molar equivalent of bis-bromomethyl compound with one molar equivalent of free base, two molar equivalents of hydrogen bromide are split off. The hydrogen bromide is preferably bound by an excess of the base used. The reaction is performed at a temperature of ca. 10 to C.

The starting material for the preparation of the compounds of Formula Ia \S/LSJ (Ia) Br llir \s/\S II(a) can be produced, e.g. starting with the thieno[2,3-b] [1] benzothiepin-4(5H)-one described in the literature [cp. M. Rajsner et al., Farmaco ('Pavia), Ed. Sci. 23, 140 148 (1968)]. This ketone is alkylated with a methyl halide, e.g. with methyl iodide, preferably in an inert solvent, e.g. in a mixture of benzene and toluene, in the presence of a condensation agent, e.g. sodium amide, to give 5-methylthieno[2,3-b] [1]benzothiepin 4(5) one. The alkylation product can be reacted according to Grignard with a methyl halide, e.g. with methyl iodide, in an inert solvent, e.g. in benzene, in the presence of magnesium to give 4,5-dimethyl-4,S-dihydrothieno[2,3-b][l] benzothiepin-4-ole. This compound is boiled with dilute acid, e.g. with diluted hydrochloric acid. The crude reac tion product is subsequently converted with ethanolic potassium hydroxide solution into 4,5-dimethylthieno [2,3-b][l]benzothiepin. The dimethylderivative can be brominated with N-bromosuccinimide in an inert solvent, e.g. carbon tetrachloride, in the presence of benzoyl peroxide to give the corresponding 4,5-'bis-bromomethyl derivative of Formula 11a.

The starting material for the preparation of the compounds of Formula Ib 1 20 CHz ii i wherein R has the meaning given in Formula I, the 4,5- bisbromomethylthieno[3,2-b] [l]benzothiepin of the Formula IIb vent, e.g. in benzene, in the presence of magnesium to give 4,5-dimethyl 4,5 dihydrothieno[3,2-b][1]benzothiepin-4-ole. This compound is boiled with dilute acid, e.g. with diluted hydrochloric acid. The crude reaction product is subsequently converted with ethanolic potassium hydroxide solution into 4,5-dimethylthieno[3,2-b] [1]benzothiepin. The dimethyl derivative can be brominated with N-bromosuccinimide in an inert solvent, e.g.,

carbon tetrachloride, in the presence of benzoyl peroxide to the corresponding 4,5-his-bromomethyl derivative of Formula Ilb.

Using a second process according to the invention, a compound of the Formula I of which the radical R is hydrogen is obtained by hydrolyzing a compound of the Formula IV:

wherein X and Y have the meaning given under Formula I, and Ac represents the acyl radical of an organic acid; and, optionally, converting an obtained compound of the Formula I, wherein R represents hydrogen into an addition salt with an inorganic or organic acid.

As acyl radical in the starting materials of the Formula IV, Ac is, in particular, the cyano or chlorocarbonyl group, an alkanoyl or arenecarbonyl group, or the radical of a monofunctional derivative of carbonic acid, thiocarbonic acid, or dithiocarbonic acid. Mentioned as examples are: for alkanoyl or arenecarbonyl groups the acetyl or benzoyl group, for radicals of monofunctional derivative of carbonic acid, thiocarbonic acid or dithiocarbonic acid: the methoxycarbonyl, ethoxycarbonyl, tert.butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methoxythiocarbonyl, ethoxythiocarbonyl, methylthiothiocarbonyl, or ethylthiothiocarbonyl group.

The hydrolysis of compounds of the Formula IV is performed, e.g. by heating such compounds for several hours in an alkanolic or aqueous/alkanolic alkali hydroxide solution, e.g. by boiling in a mixture of potassium or sodium hydroxide with ethanol or methanol, and a little water. Instead of lower alkanols, it is also possible to use other solvents containing hydroxyl groups, such as ethylene glycol or its lower monoalkyl ethers. Furthermore, especially compounds of the Formula IV wherein Ac is the cyano group can also be hydrolyzed by being heated with a mineral acid in organic/aqueous or aqueous medium, e.g. by being boiled for several hours in a mixture of phosphoric acid and formic acid, or by being heated for several hours in 48% hydrobromic acid to ca. 60 to C.

The starting materials of the Formula IV are for their part produced, e.g. fromcompounds of the Formula V:

at room temperature or at elevated temperatures, an organic acyl halide, e.g. a cyanogen halide, especially cyanogen bromide, also phosgene, a chloroformic acid alkyl ester, the chloroformic acid phenyl ester or -benzyl ester, the chloride or bromide of a lower alkanoic acid or of an arenecarboxylic acid, particularly acetyl chloride, acetyl bromide, or benzoyl chloride, whereby, according to the von Braun-reaction, the desired acylation occurs with liberation of an R -halide, e.g. an alkyl, allyl or a benzyl halide. The reaction is carried out in an inert organic solvent such as, e.g. chloroform or benzene, or optionally also in excess acyl halide.

Starting materials of the Formula V are, on the other hand, produced analogously to the first process by reacting the compound of Formula II with an amine of the General Formula V1:

wherein R represents a lower alkyl group, the allyl or the benzyl group.

The production of the applied starting compound of Formula II has been described following on the first process.

The compounds of the General Formula I obtained by the process according to the invention can, optionally, be converted in the usual manner into their addition salts with inorganic and organic acids. For example, to a solution of a compound of the Formula I in an organic solvent is added the acid desired as the salt component, or a solution of the acid. For the reaction are preferably chosen organic solvents in which the formed salt is diflicultly soluble, so that it can be separated by filtration. Such solvents are, e.g. methanol, acetone, methyl ethyl ketone, acetone/ethanol, methanol/ether, or ethanol/ether. For use as medicaments it is possible to use, instead of free bases, pharmaceutically acceptable acid addition salts, i.e. salts with such acids of which the anions are not toxic in the case of the dosages in question. Furthermore, it is advantageous if the salts to be used as medicaments crystallize well and are not, or only slightly, hygroscopic. For salt formation with compounds of the Formula I it is possible to use, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphom'c acid, ethanesulphonic acid, fi-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicyclic acid, phenylacetic acid, mandelic acid and embonic acid.

As already mentioned, the new active substances are administered orally, rectally, or parenterally. The dosage depends on the manner of administration, the species, the age, and on the individual condition. The daily dosages of the free bases or of pharmaceutically acceptable salts thereof vary between 0.1 mg./kg. and mg./kg. for warm-blooded animals. Suitable dosage units, such as drages, tablets, suppositories or ampoules, preferably contain 2-150 mg. of an active substance according to the invention.

Dosage units for oral administration preferably contain as active substance between 1 and 90% of a compound of the Formula I, or of a pharmaceutically acceptable salt of such a compound. They are produced by combining the active substance, e.g. with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or drage'e cores. The drage cores are coated, e.g. with conc. sugar solutions which may also contain, e.g. gum arabic, talcum and/ or titanium dioxide; or they are coated with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyestuffs may be added to these coatings, e.g. for identification of the varying dosages of active substance.

Further dosage units suitable for oral administration are hard gelatine capsules, as well as soft closed capsules made from gelatine and a softener such as glycerin. The hard capsules contain the active substance preferably as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and, optionally, stabilizers such as sodium metabisulphite (Na S O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby likewise stabilizers may be added.

Suitable dosage units for rectal administration are, e.g. suppositories consisting of a combination of an active substance with a fatty base. Also suitable are gelatine rectal capsules containing a combination of the active substance with polyethylene glycol.

Ampoules for parenteral administration, especially intramuscular administration, preferably contain as active substance a water-soluble salt in a concentration of preferably 0.5-5%, optionally together with suitable stabilizers and buffer substances, in aqueous solution.

The following examples further illustrate the production of compounds of Formula I and of intermediate products not hitherto described; the examples in no way limit, however, the scope of the invention. The temperatures are given in degrees centigrade.

EXAMPLE 1 (a) An amount of 16 g. of 4,5bis-bromomethylthieno [2,3-b][1]benzothiepin is dissolved in 96 ml. of abs. benzene. This solution is added dropwise at 40, within one hour, to a solution of 37.5 g. of methylamine in 225 ml. of methanol. The reaction mixture is stirred for a further hour at 50, and the solvent and the excess methylamine are subsequently distilled 01f. To the residue are added 50 ml. of water, and the formed emulsion is extracted with ether. The ethereal solution is washed with water, dried over potassium carbonate, and concentrated by evaporation. The residue, 2-methyl-2,3-dihydro-1H- thieno[2,3':2,3] [1]benzothiepino[4,-5-c]pyrrole, is a viscous oil. An amount of 8.5 g. of obtained crude base is dissolved in 40 ml. of abs. acetone, and 3.0 g. of methanesulphonic acid are carefully added, whereupon the methanesulphonate crystallizes out, which, after recrystallization from absolute ethanol, melts at 224-225 yield 9.5 g., 64% of the theoretical value.

The starting material is produced as follows:

(b) To a solution of 290 g. of thieno[2,3-b][1]benzo thiepin-4(5H)-one [cp. M. Rajsner et al., Farmaco (Pavia), Ed. Sci. 23, 140-148 (1968)], MP. 122-123", in 2,870 litres of absolute benzene is added dropwise, within 30 minutes, a suspension of 56 g. of sodium amide in ml. of absolute toluene at 60-70"; the mixture is then refluxed for 2 hours. The obtained suspension is thereupon cooled to 45 and 281 g. of methyl iodide are added dropwise within one hour, whereby the temperature is maintained between 40 and 45. The reaction mixture is stirred for 40 hours at this temperature; a further 101 g. of methyl iodide are then added, and the reaction mixture heated for a further 24 hours to 55-60 it is subsequently refluxed for 24 hours. The suspension is then cooled to 10, and 300 ml. of water are added. The organic phase is separated, washed with water, dried over sodium sulphate, and completely concentrated in vacuo. The residue, which is purified by fractionated crystallization from methanol, yields 5-methylthieno[2,3-b] [l] benzothiepin-4(5H)-one, M.P. l07l08; yield 162 g., 53% of the theoretical value.

(c) To a Grignard solution prepared from 30 g. of magnesium, 400 ml. of abs. ether and 172 g. of methyl iodide is added dropwise in the course of two hours, with good stirring, a solution of 150 g. of 5-methylthieno[2,3-b][1]benzothiepin-4(5H)-one in 600 ml. of absolute benzene, whereby a reaction temperature of -5 to is maintained. The reaction mixture is subsequently heated to 45, and is stirred at this temperature for a further 15 hours. The mixture is then cooled to 0, and is stirred into a solution of 340 g. of ammonium chloride in 1 litre of ice Water. The organic phase is separated, and the aqueous phase extracted with benzene. The combined organic solutions are washed with water, dried over sodium sulphate, and concentrated in vacuo. The residue, which is recrystallized from methanol, yields 4,5-dimethyl-4,5-dihydrothieno[2,3 b][1]benzothiepin- 4-ole, M.P. 118-120"; yield 135 g., 84.5% of the theoretical value.

((1) An amount of 135 g. of 4,5-dimethyl-4,5-dihydrothieno[2,3-b [1]benzothiepin-4-ole is refluxed in 700 ml. of 2-11 hydrochloric acid for 5 hours with stirring. The mixture is then cooled to 20, extracted with ether, the organic phase washed with water, dried over potassium carbonate, and concentrated by evaporation. The residue is dissolved in 675 ml. of abs. ethanol; to the solution are then added 135 g. of potassium hydroxide, and the mixture is afterwards refluxed for 36 hours. The reaction mixture is then poured on to water, and the crude product extracted with ether. The ether solution is washed with water, dried over potassium carbonate, and concentrated by evaporation. The residue, 4,5-dimethylthieno[2,3-b] [1]benzothiepin, melts, after recrystallization from petroleum ether, at 6971; yield 94 g., 74.5% of thetheoretical value.

(e) An amount of 34 g. of 4,5-dimethylthieno[2,3-b] [l]benzothiepin is dissolved in 630 ml. of carbon tetrachloride, and to the solution are added 49.5 g. of N- bromosuccinimide and 0.35 g. of dibenzoyl peroxide. By exposure to two ZOO-watt lamps, or to a UV-lamp, the mixture is heated to boiling whilst stirring is maintained. The mixture is kept boiling until all the N-bromosuccnimide has been reacted, which takes about 2 hours. The reaction mixture is thereupon cooled to 20, and is separated from the succinimide by filtration. The filtrate is Washed with water, dried over sodium sulphate, and concentrated completely in vacuo. The residue, which is recrystallized from benzene, yields 4,5-bis-bromomethylthieno[2,3-b][1]benzothiepin, M.P. 13l-134; yield 48 g., 86% of the theoretical value.

EXAMPLE 2 Analogously to Example 1(a) are produced the following final products:

(a) from 5.5 g. of 4,5-bis-bromomethylthieno[2,3-b][1] benzothiepin and 12 g. of ethylamine in 75 ml. of methanol: 2-ethyl-2,3-dihydro 1H thieno[2',3:2,3] [l]benzothiepino[4,5 c]pyrrole (crude product), methane sulphonate: M.P. 205-207 (from abs. ethanol); yield 3 g., 57% of the theoretical value;

(b) from 6 g. of 4,S-bis-bromomethylthieno[2,3-b][1] benzothiepin and 9.15 g. of isopropylamine in 33 ml. of methanol: 2-isopropyl-2,3-dihydro-lH-thieno[2,3': 2,3][1]benzothiepino[4,5-c1pyrrole (crude product), methane sulphonate: M.P. 250-252 (from abs. ethanol); yield 4.9 g., 83% of the theoretical value;

(c) from 6 g. of 4,5-bis-bromomethylthieno[2,3-b][1] benzothiepin and 9.15 g. of propylamine in 33 ml. of methanol: 2-propyl-2,3-dihydro 1H thieno[2,3': 2,3] 1 benzothiepino [4,5 -c] pyrrole (crude product), methane sulphonate: M.P. 220-221 (from isopropanol), yield 4.9 g., 76% of the theoretical value;

(d) from 6 g. of 4,5-bis-bromomethylthieno[2,3-b][1] benzothiepin and 10.95 g. of butylamine in 33 ml. of methanol: 2-butyl-2,3-dihydro-IH-thieno[2,3:2,3] [1] benzothiepino[4,5-c]pyrrole (crude product), methane 8 sulphonate: M.P. 213-215 (from abs. ethanol); yield 4.2 g., 68% of the theoretical value;

(e) from 20.1 g. of 4,S-bis-bromomethylthieno [2,3-b] [1] benzothiepin and 28.5 g. of allylamine in 74 ml. of methanol: 2-allyl-2,3-dihydro-lH-thieno[2',3':2,3][1] benzothiepino[4,5-c]pyrrole, M.P. -96 (from benzene); yield 10 g., 67.5% of the theoretical value; methane sulphonate: M.P. 222-225 (from isopropanol) (f) from 12.0 g. of 4,5-bis bromomethylthieno[2,3-b] [1] benzothiepin and 21.9 g. of isobutylamine in 66 ml. of methanol: 2-isobutyl-2,3-dihydro-IH-thieno[2,3': 2,3][1]benzothiepino[4,5-c1pyrrole, crude product; methanesulphonate: M.P. 225-227 {from abs. ethanol); yield 8.0 g., 65% of the theoretical value.

(g) from 12.0 g. of 4,S-bis-bromomethylthieno[2,3-b] [l] benzothiepin and 21.9 g. of sec. butylamine in 66 ml. of methanol: 2-(2-buty1)-2,3-dihydro-lH-thieno [2,3:2, 3] [1]benzothiepino[4,5 c]pyrrole, M.P. 104-106 (from petroleum ether); yield 7.3 g., 78% of the theoretical value; methane sulphonate: M.P. 238-240 (from abs. ethanol).

EXAMPLE 3 '(a) An amount of 4.3 g. of 2,3-dihydro-1H-thieno[2, 3 2,3] 1 benzothiepino [4,5 -c] pyrrole-2-carboxylic acid ethyl ester is refluxed with a solutoin of 4.3 g. of potassium hydroxide in 43 ml. of abs. ethanol for one hour. The ethanol is then distilled off in vacuo from the reaction mixture. Water is added to the residue, and the crude product extracted with ether. The ethereal solution is washed With water, dried over potassium carbonate, and

concentrated by evaporation. An amount of 1.83 g. of.

crude, 2,3-dihydro-lH-thieno [2,3 2,3] [1]benzothiepino [4,5-c]pyrrole remains behind. The obtained crude base is dissolved in 30 ml. of abs. acetone, and neutralized with 0.68 g. of methanesulphonic acid, whereupon the methane sulphonate crystallizes out, which, after recrystallization from isopropanol, melts at 215-218"; yield 2.5 g., 56% of the theoretical value.

The starting product is produced as follows:

(b) An amount of 6 g. of 2-allyl-2,3-dihydro-lH-thieno [2',3':2,3][1]benzothiepino[4,5-c]pyrrole is dissolved in 50 ml. of abs. benzene, and the solution refluxed with stirring. A solution of 3.3 g. of chloroformic acid ethyl ester in 50 ml. of abs. benzene is added dropwise within one hour, and the formed allyl chloride simultaneously distilled ofi. After completion of the dropwise addition, boiling is continued for a further hour, and the solution cooled to room temperature. The reaction solution is washed with 2-n hydrochloric acid and then with water; it is afterwards dried over sodium sulphate, and concentrated in vacuo to a small volume, whereupon 2,3-dihydro- 1H-thieno[2,3':2,3] [1]benzothiepino[4,5 c] pyrrole 2- carboxylic acid ethyl ester, M.P. l56l59, crystallizes out; yield 5.5 g., 83% of the theoretical value.

EXAMPLE 4 (a) An amount of 20.1 g. of 4,5-bis-bromomethylthieno [3,2-b][1]benzothiepin is dissolved in ml. of abs. benzene. This solution is added dropwise at 40 C. within .one hour, with stirring, to a solution of 46.5 g. of methylamine in 280 ml. of methanol. The reaction mixture is stirred for a further hour at 50, and the solvent and the excess methylamine are subsequently distilled ofi. To the residue are added 65 ml. of water, and the formed emulsion is extracted with ether. The ethereal solution is washed with water, dried over potassium carbonate, and concentrated by evaporation. The residue, 2-methyl-2,3-dihydro- 1H-thieno[3',2':2,3] [1]benzothiepino[4,5-c1pyrrole, is a viscous oil.

An amount of 6.25 g. of the obtained crude base is dissolved in 35 ml. of abs. acetone, and 2.22 g. of methanesulphonic acid are carefully added, whereupon the methanesulphonate crystallizes out; this melts, after recrystillization from abs. ethanol/ether, at 217-219"; yield 6.5 g., 35.5% of the theoretical value.

The starting material is produced as follows:

(b) To a solution of 290 g. of thieno[3,2-b] [1]benzothiepin-4(5H)-one (cp. I. R. Geigy A.G., Belgian Pat. No. 715,363), M.P. 138140, in 2,870 litres of abs. benzene is added dropwise, within 30 minutes at 60-70, a suspension of 56 g. of sodium amide in 130 ml. of abs. toluene; the mixture is then refluxed for two hours. The obtained suspension is afterwards cooled to 45, and 281 g. of methyl iodide are added dropwise within one hour, whereby the temperature is maintained between 40 and 45. The reaction mixture is stirred for a further 40 hours at this temperature; a further 101 g. of methyl iodide are added and the reaction mixture is maintained for a further 24 hours at 55-60; it is then refluxed for 24 hours. The suspension is then cooled to 10, and 300 ml. of water are added dropwise. The organic phase is separated, washed with water, dried over sodium sulphate, and concentrated in vacuo. The residue, which is purified by fractionated crystallization from methanol, yields: 5-methylthieno[3,2-b] [1]benzothiepin 4 (5H)- one, M.P. 110-111"; yield 168 g., 54.5% of the theoretical value.

(c) To a Grignard solution prepared from 30 g. of magnesium, 400 ml. of abs. ether and 172 g. of methyl iodide is added dropwise in the course of two hours, with good stirring, a solution of 150 g. of 5-methylthieno[3,2-b] [1]benzothiepin-4-(5H)-one in 600 ml. of abs. benzene, whereby a reaction temperature of 5 to is maintained. The reaction mixture is subsequently heated to 45 and is stirred at this temperature for a further 15 hours; the mixture is then cooled to 0, and is stirred into a solution of 340 g. of ammonium chloride in 1000 ml. of ice water. The organic phase is separated, and the aqueous phase extracted with benzene. The combined solutions are washed with water, dried over sodium sulphate, and concentrated in vacuo. Obtained as residue are 160 g. of 4.5- dimethyl-4,5-dihydrothieno[3,2-b] [1]benzothiepin-4 ole in the form of viscous oil.

(d) An amount of 129 g. of the crude product obtained according to (c) is refluxed in 645 ml. of 2-n hydrochloric acid for 5 hours whilst stirring is maintained. The mixture is then cooled to 20, extracted with ether, the organic phase washed with water, dried over potassium carbonate, and concentrated by evaporation. The residue is dissolved in 645 ml. of abs. ethanol; to the solution are then added 129 g. of potassium hydroxide, and the mixture is refluxed for 36 hours. The reaction mixture is then poured on to water, and extracted with ether. The organic phase is washed with water, dried over potassium carbonate, and concentrated by evaporation. The residue, 4,5-dimethylthieno[3,2b] [1]benzothiepin, melts, after recrystallization from a solvent mixture of one part of ether and two parts of methanol, at 6970; yield 70 g., 58.5% of the theoretical value.

(e) An amount of 55 g. of the compound obtained according to (cl) is dissolved in 1,130 litres of carbon tetrachloride, and to the solution are added 81 g. of N- bromosuccinimide and 0.56 g. of dibenzoyl peroxide. By exposure to two ZOO-watt lamps, or to a UV-lamp, the mixture is refluxed whilst stirring is maintained. Boiling proceeds until all the N-bromosuccinimide has been reacted, which takes about 30 minutes. The reaction mixture is then cooled to 20, and is separated from the succinirnide by filtration. The filtrate is Washed with water, dried over sodium sulphate and completely concentrated in vacuo. The residue, which is recrystallized from methanol, yields 4,5 bis-bromoethylthieno[3,2-b][1]benzothiepin, M.P. 100102; yield 68 g., 75% of the theoretical value.

10 EXAMPLE 5 Analogously to Example 1(a) are produced the following final products:

(a) from 10.0 g. of 4,5-bis-bromomethylthieno[3,2-b[1] benzothiepin and 22.5 g. of ethylamine in ml. of methanol: crude 2-ethyl-2,3-1H thieno[3,2':2,3][l] benzothiepino[4,5-c]pyrrole; methane sulphonate, M.P. 208210 (from abs. ethanol); yield 3.1 g., 32.6% of the theoretical value;

(b) from 10.0 g. of 4,5-bis-bromomethylthieno[3,2-b][l] benzothiepin and 14.8 g. of isopropylamine in 55 ml. of methanol: crude 2-isopropyl-2,3-dihydro-lH-thieno[3, 2':2,3][1]benzothiepino [4,5-c]pyrrole; methane. sulphonate, M.P. 232234 (from isopropanol); yield 4.4 g., 45% of the theoretical value;

(c) from 10.0 g. of 4.5-bis-bromomethylthieno[3,2-b][1] benzothiepin and 14.8 g. of propylamine in 55 ml. of methanol: crude 2-propyl-2,3-dihydro-lH-thieno[3,2': 2,3][l]benzothiepino[4,5-c]pyrrole; methane sulphonate, M.P. 211-213 (from abs. ethanol/ether); yield 4.5 g., 45 45% of the theoretical value;

(d) from 10.0 g. of 4,5-bis-bromomethylthieno[3,2-b] [1] benzothiepin and 18.25 g. of butylamine in 55 ml. of methanol: crude 2-butyl-2,3-dihydro-1H-thieno[3,2:2, 3] [1]benzothiepino [4,5-c]pyrrole; methane sulphonate, M.P. 206208 (from abs. ethanol/ether); yield 4.4 g., 43 of the theoretical value; and

(e) from 22.1 g. of 4,5-bis-bromomethylthieno[3,2-b][1] benzothiepin and 31.5 g. of allylamine in 100 ml. of methanol: crude 2-allyl-2,3-dihydr0-lH-thieno [3 ,2' 2, 3] [l]benzothiepino[4,5-c] pyrrole; methane sulphonate, M.P. 217-220 (from abs. ethanol/ether); yield 11.5 g., 53.5% of the theoretical value.

EXAMPLE 6 (a) An amount of 3.5 g. of 2,3-dihydro-1H-thieno[3, 2':2,3][1]benzothiepin[4,5-c]pyrrole-2 carboxylic acid ethyl ester is refluxed with a solution of 3.5 g. of potassium hydroxide in 35 ml. of abs. ethanol for 4 hours. The ethanol is then distilled otf in vacuo from the reaction mixture. Water is added to the residue, and the suspension is extracted with ether. The ethereal solution is washed with water, dried over potassium carbonate, and concentrated by evaporation. Remaining as residue is: 2,3- dihydro 1H thieno[3,2:2,3][-]benzothiepino[4,5-c] pyrrole as crude product.

An amount of 2 g. of the crude base is dissolved in 20 ml. of abs. acetone, and the solution neutralized with 0.75 g. of methanesulphonic acid, whereupon methane sulphonate crystallizes out, which, after recrystallization, melts at 210-212; yield 1.7 g., 45.5% of the theoretical va ue.

The starting compound is produced as follows:

(b) An amount of 6.0 g. of 2-allyl-2,3-dihydro-1H- thieno [3,2 :2,3] [1]benzothiepino[4,5-c]pyrrole is dissolved in 50 ml. of abs. benzene, and the solution heated to boiling whilst being stirred. A solution of 3.3 g. of chloroformic acid ethyl ester in 50 ml. of abs. benzene is then added dropwise within one hour, the

formed allyl chloride simultaneously distilled off, and

refluxing continued for a further hour. The benzene solution cooled to room temperature is washed with 2-n hydrochlroic acid and then with water; it is afterwards dried over sodium sulphate, and concentrated in vacuo to a small volume, whereupon 2,3-dihydro-1H-thieno [3,2 2,3] 1]benzothiepino [4,5 -c] pyrrole Z-carboxylic acid ethyl ester, M.P. 121124, crystallizes out; yield 5.56 g., 84% of the theoretical value.

EXAMPLE 7 An amount of 250 g. of 2,3-dihydro-1H-thieno[2,3': 2,3] [1]benzothiepino[4,5 c]pyrrole methanesulphonate is mixed with 175.80 g. of lactose and 169.70 g. of potato starch; the mixture is then moistened with an alcoholic solution of g. of stearic acid, and granulated through a sieve. After the granulate has dried, 160 g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed in; the mixture is then pressed to form 10,000 tablets each weighing 100 mg. and each containing 25 mg. of active substance. If required, the tablets can be provided with grooves for a more precise adjustment of the dosage amount.

EXAMPLE 8 A granulate is produced from 250 g. of 2,3-dihydro 1H thieno[2,3':2,3][1]benzothiepino[4,5 c]pyrrole methanesulphonate, 175.90 g. of lactose, and the alcoholic solution of 10 g. of stearic acid; after drying, the granulate is mixed with 56.60 g. of colloidal silicon di-f oxide, 165 g. of talcum, g. of potato starch and 2.50 g. of magnesium stearate; and the mixture pressed to form 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 502.28 g. of crystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestuff, and 1.5 g. of titanium dioxide, and then dried. The obtained drages each weigh 120 mg. and each contain mg. of active substance.

EXAMPLE 9 To produce 1000 capsules each containing 25 mg. of active substance, 25 g. of 2,3-dihydro-lH-thieno[2',3':2, 3] [11benzothiepino [4,5 -c]pyrrole methansulphonate are mixed with 248 g. of lactose; the mixture is evenly moistened with an aqueous solution of 2 g. of gelatine, and is then granulated through a'suitable sieve (e.g. Sieve IH according to Ph. Helv. V). The granulate is mixed with 10 g. of dried maize starch and 15 g. of talcum, and the mixture is evenly filled into 1000 hard gelatine capsules, size 1.

EXAMPLE 10 A suppository foundation substance is prepared from 2.5 g. of 2,3-dihydro-1H-thieno[2',3':2,3][1]benzm thiepino [4,5-c]pyrrole methansulphonate and 167.5 g. of adeps solidus; it is then used to fill 100 suppositories each containing 25 mg. of active substance.

EMMPLE 11 A solution of 25 g. of 2,3-dihydro-lH-thieno[2',3':2,3] [1]benzothiepino[4,5-c]pyrrole methansulphonate in one litre of water is filled into 1000 ampoules, and then sterilized. An ampoule contains a 2.5% solution of 25 mg. of active substance.

EXAMPLE 12 An amount of 250 g. of 2-ethyl-2,3-dihydro-lH-thieno [3',2:2,3] [1]benzothioepino[4,5-c1pyrrole methanesul phonate is mixed with 175.80 g. of lactose and 169.70 g. of potato starch; the mixture is then moistened with an alcoholic solution of 10 g. of stearic acid, and granulated through a sieve. After the granulate has dried, 160 g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed in; the mixture is then pressed to form 10,000 tab-lets each weighing 100 mg. and each containing 25 mg. of active substance. If required, the tablets can be provided with grooves for a more precise adjustment of the dosage amount.

EXAMPLE 13 A granulate is produced from 250 g. of 2-ethyl-2,3-dihydro 1H thieno[3,2':2,3][1]benzothiepino[4,5-c] pyrrole methanesulphonate, 175.90 g. of lactose, and the alcoholic solution of 10 g. or stearic acid; after drying, the granulate is mixed with 56.60 g. of colloidal silicon dioxide, 165 g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate; and the mixture pressed to form 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 502.28 g. of crystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestutf, and 1.5 g. of titanium dioxide, and then dried. The obtained drages each weigh 120 mg. and each contain 25 mg. of active substance.

EXAMPLE 14 To produce 1000 capsules each containing 25 mg. of active substance, 25 g. of 2-ethyl-2,3-dihydro-lH-thieno [3,2':2,3] [1]benzothiepino[4,5 c]pyrrole methanesulphonate are mixed with 248 g. of lactose; the mixture is evenly moistened with an aqueous solution of 2 g. of gelatine, and is then granulated through a suitable sieve (e.g. Sieve III according to Ph. Helv. V). The granulate is mixed with 10 g. of dried maize starch and 15 g. of talcum, and the mixture is evenly filled into 1000 hard ge'latine capsules, size 1.

EXAMPLE 15 A suppository foundation substance is prepared from 2.5 g. of 2-ethyl-2,3-dihydro-lH-thieno[3,2:2,3] [1] benzothiepino [4,5 c]pyrrole methanesulphonate and 167.5 g. of adeps solidus; it is then used to fill suppositories each containing 25 mg. of active substance.

EXAMPLE 16 A solution of 25 g. of 2-ethyl-2,3-dihydro-lH-thieno [3,2':2,3] [1]benzothiepino[4,5 c]pyrrole methanesulphonate in one litre of water is filled into 1000 ampoules, and then sterilized. An ampoule contains a 2.5% solution of 25 mg. of active substance.

It is also possible to use, as active substance for tablets, drag'es, capsules, suppositories and ampoules, the same amount of the following compounds:

2-methyl-2,3-dihydro 1H thieno[3',2':2,3] [llbenzothiepino [4,5-c]pyrrole methanesulphonate.

2-butyl-2,3-dihydro 1H thieno[3',2':2,3][1]benzothiepino[4,5-c] pyrrole methanesulphonate.

2-methyl-2,3-dihydro 1H thieno [2',3':2,3] [l]benzothiepino[4,5-c] pyrrole methanesulphonate.

2-ethyl-2,3-dihydro 1H thieno[2,3:2,3][1]benzothiepino'[4,5-c]pyrrole methanesulphonate.

What is claimed is:

'1. A compound of the Formula II II Br BrH 3. The compound according to claim 1 which is 4,5- bis-bromomethylthieno [2,3-b] 1]benzothiepin.

References Cited UNITED STATES PATENTS 3,682,959 8/1972 Blattner et a1. 260-3269 HENRY R. JILES, Primary Examiner C. M. S. JAISLE, Assistant Examiner 

